TY - JOUR T1 - Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice JF - bioRxiv DO - 10.1101/2020.12.28.424586 SP - 2020.12.28.424586 AU - Nina Martino AU - Ramon Bossardi Ramos AU - Shuhan Lu AU - Kara Leyden AU - Lindsay Tomaszek AU - Sudeshna Sadhu AU - Gabrielle Fredman AU - Ariel Jaitovich AU - Peter A. Vincent AU - Alejandro P. Adam Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/06/11/2020.12.28.424586.abstract N2 - SOCS3 is the main inhibitor of the JAK/STAT3 pathway. This pathway is activated by interleukin 6 (IL-6), a major mediator of the cytokine storm during shock. To determine its role in the vascular response to shock, we challenged mice lacking SOCS3 in the adult endothelium (SOCS3iEKo) with a non-lethal dose of lipopolysaccharide (LPS). SOCS3iEKo mice died 16-24 hours post-injection after severe kidney failure. Loss of SOCS3 led to an LPS-induced type I interferon-like program, and high expression of pro-thrombotic and pro-adhesive genes. Consistently, we observed intraluminal leukocyte adhesion and NETosis, as well as retinal venular leukoembolization. Notably, heterozygous mice displayed an intermediate phenotype, suggesting a gene dose effect. In vitro studies were performed to study the role of SOCS3 protein levels in the regulation of the inflammatory response. In HUVEC, pulse-chase experiments showed that SOCS3 protein has a half-life below 20 minutes. Inhibition of SOCS3 ubiquitination and proteasomal degradation leads to protein accumulation and a stronger inhibition of IL-6 signaling and barrier function loss. Together, our data demonstrates that the regulation of SOCS3 protein levels is critical to inhibit IL-6-mediated endotheliopathy during shock and provides a promising new therapeutic avenue to prevent MODS though stabilization of endothelial SOCS3.Competing Interest StatementThe authors have declared no competing interest. ER -